At present no tractable animal model for HIV-1 induced immunodeficiency of man exists. HIV-1 readily establishes infections of chimpanzees but no disease is induced. Our current knowledge about HIV-1 pathogenesis in vivo derives from retrospective clinical analyses and biopsies of lymphoid tissues collected from infected individuals. Studies of the closely related SIV and its infection of Asian macaques have provided useful information about the sites and kinetics of primate lentivirus infections in vivo. SIV/HIV chimeric viruses (SHIVs), carrying several HIV-1 genes, have been constructed and used to monitor the roles of the HIV-1 envelope glycoprotein in infected animals. Highly pathogenic SHIVs have recently been obtained, which induce a rapid (within 2 to 3 weeks of inoculation), irreversible depletion of CD4+ T lymphocytes in the peripheral blood of acutely infected rhesus monkeys. Infected animals survive an additional 4 to 6 months and high levels of viremia are sustained in the absence of CD4+ T lymphocytes by macrophage in lymphoid tissues and the gastrointestinal tract. We have investigated whether specific changes in the viral genome accompany the transition from the T cell to the macrophage phase of SHIV infected macaques. Using two different, but related, uncloned virus stocks to inoculate 7 rhesus monkeys, specific amino acid changes (deletions and substitutions) were introduced into the V2 region of gp120 during independent in vivo infections in all of the infected monkeys. No changes were observed in other regions of the viral envelope glycoprotein. A subset of these late phase SHIV variants, which replicated to high titers in cultured alveolar macrophage (AM), carried envelopes with a specific deletion and loss of a V2 glycosylation site. Pig-tailed macaques (Macaca nemestrina) and rhesus monkeys (Macaca mulatta), two non-human primate species commonly used to model HIV infection, can exhibit distinct clinical courses following infection with different primate lentiviruses. As an initial step in assessing the role of MHC class I restricted immune responses to these infections, we have cloned and characterized classical MHC class I genes of pig-tailed macaques and have identified 19 MHC class I alleles (Mane), orthologous to rhesus macaque MHC-A, -B and -I genes. Both Mane-A and B loci were found to be duplicated and no MHC-C locus was detected. Pig-tailed and rhesus macaque MHC-A alleles form two groups as defined by 14 polymorphisms affecting mainly their B peptide-binding pockets. Furthermore, an analysis of multiple pig-tailed monkeys revealed the existence of three MHC-A haplotypes.